COCAINE-INDUCED PREPRODYNORPHIN mRNA EXPRESSION IN THE STRIATAL MATRIX IS DEPENDENT ON SEROTONIN K.A. Keefe, C. Xochime, G.R. Hanson*, D.H. Adams. Dept of Pharm/Tox, Univ Utah, SLC, UT 84112 Methamphetamine (METH) and cocaine (COC) increase preprodynorphin (PPD) mRNA levels in striatum. A single, high dose of METH increases PPD mRNA selectively in the patch division of rostral striatum, whereas COC increases it in both patch and matrix. Activation of dopamine D1 receptors is necessary for both COC- and METH-induced increases in PPD mRNA. However, 5-HT may contribute to the regional selectivity of the effects of COC and METH on PPD mRNA, as 5-HT receptor activation alters PPD mRNA expression, and 5-HT2 receptors have an unequal distribution in relation to the striatal patch and matrix divisions. To test the role of 5-HT in COC- and METH-induced increases in PPD mRNA, we depleted 5-HT with p-chloroamphetamine (PCA; 8 mg/kg) one week prior to COC (30 mg/kg, i.p.) or METH (15 mg/kg, s.c.) administration, and examined PPD mRNA levels using in situ hybridization histochemistry. In control rats, COC increased PPD mRNA homogeneously in rostral striatum, whereas METH increased PPD mRNA selectively in the patch division, as previously reported. PCA-induced loss of 5-HT did not affect basal or METH-induced PPD mRNA expression in rostral striatum. In contrast, the PCA-induced loss of 5-HT selectively inhibited the matrix, but not the patch, component of COC-induced PPD mRNA expression in rostral striatum. These findings suggest that COC-induced PPD mRNA expression in the matrix division of rostral striatum is secondary to increases in 5-HT, whereas the effects of METH on PPD mRNA expression are independent of 5-HT function. The role of 5-HT2A and 5-HT2C receptors in the effects of COC is currently being examined. Supported by DA09407, DA13367, and an AFPE fellowship